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METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.

ABSTRACT: The prevalence of childhood obesity and insulin resistance is rising, increasing the risk of diabetes mellitus type 2. To prevent these complications, lifestyle intervention is the corner stone in treatment. However, long-term efficacy of lifestyle intervention is questionable. In addition to lifestyle intervention, pharmacological treatments have been explored. Metformin has been shown to be moderately effective to reduce BMI in obese adolescents with hyperinsulinemia. However, data on pharmacokinetics and long-term efficacy and safety are lacking as well as an evidence-based dosing regimen for this age group. The primary objective of the METFORMIN study is to determine the effect of adding metformin treatment to lifestyle intervention in reducing BMI in obese adolescents with insulin resistance. In addition, the pharmacokinetics of metformin in obese adolescents will be studied.The METFORMIN study is a multi-centre prospective study that consists of two 18-month phases: a double-blind randomized placebo-controlled trial (part 1) and an open-label follow-up study (part 2). During part 1, the participants will be given metformin 1,000 mg or placebo twice daily and will be offered a lifestyle intervention programme; 144 participants will be included, 72 in each arm. Primary endpoints are reduction in body mass index, insulin resistance, and percentage body fat.This study will provide data on short- and long-term efficacy and safety of metformin and on the pharmacokinetics of metformin in obese adolescents.ClinicalTrials.gov number NCT01487993; EudraCT nr. 2010-023980-17. Registration date: 06-01-2011.

SUBMITTER: van der Aa MP

PROVIDER: S-EPMC4053305 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.

van der Aa Marloes P MP Elst Marieke A J MA van Mil Edgar G A H EG Knibbe Catherijne A J CA van der Vorst Marja M J MM

Trials 20140605

<h4>Background</h4>The prevalence of childhood obesity and insulin resistance is rising, increasing the risk of diabetes mellitus type 2. To prevent these complications, lifestyle intervention is the corner stone in treatment. However, long-term efficacy of lifestyle intervention is questionable. In addition to lifestyle intervention, pharmacological treatments have been explored. Metformin has been shown to be moderately effective to reduce BMI in obese adolescents with hyperinsulinemia. Howeve ...[more]

PMID: 24899137

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Project description:Childhood obesity is a serious health concern affecting over 155 million children in developed countries worldwide. Childhood obesity is associated with significantly increased risk for development of type 2 diabetes, cardiovascular disease and psychosocial functioning problems (i.e., depression and decreased quality of life). The two major strategies for management of obesity and associated metabolic abnormalities are lifestyle modification and pharmacologic therapy. This paper will provide the background rationale and methods of the REACH childhood obesity treatment program.The REACH study is a 2-year multidisciplinary, family-based, childhood obesity treatment program. Seventy-two obese adolescents (aged 10-16 years) and their parents are being recruited to participate in this randomized placebo controlled trial. Participants are randomized to receive either metformin or placebo, and are then randomized to a moderate or a vigorous intensity supervised exercise program for the first 12-weeks. After the 12-week exercise program, participants engage in weekly exercise sessions with an exercise facilitator at a local community center. Participants engage in treatment sessions with a dietitian and social worker monthly for the first year, and then every three months for the second year. The primary outcome measure is change in body mass index and the secondary outcome measures are changes in body composition, risk factors for type 2 diabetes and cardiovascular disease, changes in diet, physical activity, and psychosocial well-being (e.g., quality of life). It is hypothesized that participants who take metformin and engage in vigorous intensity exercise will show the greatest improvements in body mass index. In addition, it is hypothesized that participants who adhere to the REACH program will show improvements in body composition, physical activity, diet, psychosocial functioning and risk factor profiles for type 2 diabetes and cardiovascular disease. These improvements are expected to be maintained over the 2-year program.The findings from this study will advance the knowledge regarding the long-term efficacy and sustainability of interventions for childhood obesity.ClinicalTrials.gov number NCT00934570.

Project description:BackgroundIn the United States, approximately one-third of adolescents are now overweight or obese, and one in six is obese. This financial cost and the larger nonfinancial costs of obesity make obesity prevention and management for adolescents imperative for the health of the nation. However, primary care visits are typically brief, and primary care providers may lack adequate resources to help overweight or obese adolescents to manage weight issues. To augment the efficacy of primary care visits for adolescent weight management, mobile phone technology can be used as an adjunct treatment that provides additional opportunities for encouraging improvement in lifestyle, attainment, and maintenance of healthy weight.ObjectiveThe purposes of this study were to (1) measure effects of an innovative mobile phone technology-based intervention for overweight and obese adolescents and to (2) examine the intervention's feasibility for use in primary care clinics.MethodsThe mobile phone-based intervention had three components: use of the Fitbit Flex, participation in an online educational program, and receipt of biweekly text messages during the maintenance phase. A randomized controlled study design was utilized. Data regarding anthropometrics (body mass index [BMI] and waist-to-hip ratio), blood pressure, levels of physical and sedentary activity, diet, and self-efficacy regarding physical activity and diet were collected at baseline and at 3 and 6 months after the baseline assessment.ResultsA total of 40 adolescents participated in the study. At the 6-month follow-up visit, compared to participants in the control group, the mobile phone-based intervention participants had significant improvement in BMI (z=-4.37, P=.001), diastolic blood pressure (z=-3.23, P=.001), physical activity days per week (z=2.58, P=.01), TV and computer time (z=-3.34, P=.001), servings of fruits and vegetables per day (z=2.74, P=.006), servings of soda and sweetened drinks (z=-3.19, P=.001), physical activity self-efficacy (z=2.75, P=.006), and dietary self-efficacy (z=5.05, P=.001). Medium to large effect sizes were found in these outcome variables.ConclusionsThe use of mobile technologies may offer a practical, reliable adjunct to weight management for overweight and obese adolescents in busy primary care clinics serving adolescents.Trial registrationClinicaltrials.gov NCT 01693250; https://clinicaltrials.gov/ct2/show/NCT01693250? term=Adolescent+ obesity+AND+mhealth&rank=5 (Archived by WebCite at ).

Project description:OBJECTIVE:To assess the efficacy and safety of short- term intensive hypoglycemic therapy with a triple regimen consisting of metformin, sagliptin and dapagliflozin in patients with newly diagnosed type 2 diabetes mellitus with hemoglobin Alc (HbA1c) of 9%-12%. METHODS:We prospectively enrolled 58 patients with newly diagnosed type 2 diabetes, who were treated with metformin combined with sagliptin and dapagliflozin for 12 weeks on the basis of diabetic diet and regular exercise. Blood glucose was monitored during the treatment and the changes in HbA1c, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 hPBG), fasting insulin (FINS), 2-hour postprandial insulin (2 hPINS), fasting C-peptide (F-CP), 2-hour postprandial C-peptide (2 hP-CP), and body weight after treatment as well as the incidence of hypoglycemia and adverse events associated with the treatment were recorded. RESULTS:Two patients withdrew from the study for intolerance of gastrointestinal reactions, and another 2 withdrew for inconvenience of access to the medicines. Fifty-four of the patients finally completed the study, including 34 male and 20 female patients. After 12 weeks of therapy, all the patients showed significant improvements in FBG, 2 hPBG, HbA1c, HOMA-beta and HOMA-IR (P < 0.001) with a mean reduction of HbA1c level by (4.19 ± 1.07)%, and the goal of HbA1c control to below 7.0% was achieved in 83.33% of the patients. The reduction of HbA1c was correlated with FBG (r=0.487, P=0.000), 2 hPBG (r=0.310, P=0.023), and HOMA-? (r=-0.398, P=0.003). The patients had a mean body weight loss by 2.47±3.38 kg (P < 0.001) and a mean decrease of body mass index (BMI) by 0.90± 1.18 kg/m2 (P < 0.001) after the therapy. The body weight-reducing effect was associated with the patients' baseline body weight (r=0.678, P=0.000), BMI (r=0.818, P=0.000), F-CP (r=0.282, P=0.039) and HOMA-IR (r=0.297, P=0.029). During the therapy 8 patients experienced hypoglycemic symptoms (10 times, 14.81%); 3 patients were diagnosed with hypoglycemia (blood glucose ?3.9 mmol/L, 3 times), and the overall incidence of hypoglycemia was 5.56%. No serious hypoglycemia or infections of the urinary and reproductive systems occurred in these patients. CONCLUSIONS:Short-term intensive oral hypoglycemic therapy with metformin combined with sagliptin and dapagliflozin is effective for treatment of patients with newly diagnosed type 2 diabetes with HbA1c of 9%-12% and shows a good weight-reducing effect with a low risk of hypoglycemia. The combined therapy can effectively improve ?-cell insulin secretion function, and is suitable for treatment of newly diagnosed type 2 diabetic patients with high blood glucose.

Project description:BackgroundObesity and insulin resistance (IR) are common features of polycystic ovary syndrome (PCOS). Metformin (MET) increases insulin sensitivity, but it is associated with unsatisfactory weight loss. The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes. This study aimed to explore the therapeutic effects of exenatide once-weekly (QW) combined with MET on body weight, as well as metabolic and endocrinological parameters in overweight/obese women with PCOS.MethodsFifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups: MET (500 mg three times a day [TID]) or combination treatment (COM) (MET 500 mg TID, exenatide 2 mg QW) for 12 weeks. The primary outcomes were anthropometric changes associated with obesity, and the secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein.ResultsForty (80%) patients completed the study. COM therapy was superior to MET monotherapy in reducing weight (P = 0.045), body mass index (BMI) (P = 0.041), and waist circumference (P = 0.023). Patients in the COM group on an average lost 3.8 ± 2.4 kg compared with 2.1 ± 3.0 kg in the MET group. In the COM group, BMI and waist circumference decreased by 1.4 ± 0.87 kg/m2 and 4.63 ± 4.42 cm compared with 0.77 ± 1.17 kg/m2 and 1.72 ± 3.07 cm in the MET group, respectively. Moreover, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET (P < 0.050). Mild and moderate gastrointestinal reactions were the most common adverse events in both groups.ConclusionsCOM therapy was more effective than MET alone in reducing body weight, BMI, and waist circumference, and improving insulin sensitivity in overweight/obese women with PCOS, with acceptable short-term side effects.Trial registrationClinicalTrials.gov, NCT04029272. https://clinicaltrials.gov/ct2/show/NCT04029272.

Project description:Obesity is the leading cause of health-related diseases in the United States and World. Previously, we reported that obesity can change gut microbiota using the Zucker rat model. Metformin is an oral anti-hyperglycemic agent approved by the FDA to treat type 2 diabetes (T2D) in adults and children older than 10 years of age. The correlation of short-term metformin treatment and specific alterations to the gut microbiota in obese models is less known. Short-term metformin has been shown to reduce liver steatosis. Here we investigate the effects of short-term metformin treatment on population of gut microbiota profile in an obese rat model. Five week old obese (n = 12) female Zucker rats after 1 week of acclimation, received AIN-93 G diet for 8 weeks and then rats were randomly assigned into two groups (6 rats/group): (1) obese without metformin (ObC), or (2) obese with metformin (ObMet). Metformin was mixed with AIN-93G diet at 1,000 mg/kg of diet. Rats were weighed twice per week. All rats were sacrificed at the end of metformin treatment at 10 weeks and fecal samples were collected and kept at -80°C. Total microbial DNA was collected directly from the fecal samples used for shotgun-metagenomics sequencing and subsequently analyzed using MetaPlAn and HUMAnN. After stringent data filtering and quality control we found significant differences (p = 0.0007) in beta diversity (Aitchison distances) between the ObC vs. ObMet groups. Supervised and unsupervised analysis of the log-ratios Bacteroides dorei and B. massiliensis vs. all other Bacteroides spp., revealed that B. dorei and B. massiliensis were enriched in the ObMet group, while the remaining Bacteroides spp. where enriched in the ObC group (p = 0.002). The contributional diversity of pathways is also significantly associated by treatment group (p = 0.008). In summary, in the obese Zucker rat model, short-term metformin treatment changes the gut microbiota profile, particularly altering the composition Bacteroides spp. between ObC and ObMet.

Project description:The biologic agent ustekinumab is a human monoclonal antibody that binds to the p40 subunit shared by interleukins (ILs) 12 and 23. The antibody is able to prevent binding of cytokines to the IL-12R?1 cell surface receptor and therefore may prevent IL-23 driven activation of the IL-23/Th 17 axis of inflammation. The anti-inflammatory activity has been beneficial in adult psoriasis. Ustekinumab has been approved in the United States for the treatment of adults with psoriasis and psoriatic arthritis. Approval in children and adolescents has not been granted by the US Food and Drug Administration. Subcutaneous injections of ustekinumab are administered at baseline, week 4 and every 12 weeks thereafter, a regimen that is particularly appealing to young patients who do not like more frequent injections at home. The product is attractive because, although it works through an immune system mechanism, the selective activity is such that the drug has not been associated with many of the side effects attributed to other immunosuppressive medications. Case reports of ustekinumab for pediatric psoriasis have shown promising results, and the recent Phase III CADMUS trial tested the agent in adolescents aged 12-17 years with psoriasis, using standard dose 0.75 mg/kg (?60 kg), 45 mg (>60-?100 kg), and 90 mg (>100 kg) or half-standard dosing 0.375 mg/kg (?60 kg), 22.5 mg (>60-?100 kg), and 45 mg (>100 kg) with a loading dosage at week 0 and week 4. Psoriasis area and severity index-75 was achieved in more than three-quarters of patients in full and half dosing by 12 weeks, and psoriasis area and severity index-90 in 54.1% and 61.1% of half and full dosage by 12 weeks, respectively. Ustekinumab was generally well tolerated in adolescents, with some patients developing antibodies, and nasopharyngitis being the major adverse event. Ustekinumab is a promising agent in adolescent psoriasis that appears to be well tolerated. The best monitoring plan and usage in younger patients still remain to be defined.

Dataset Information

METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.

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METFORMIN: an efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents - study protocol of a randomized controlled study.

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